Since the inception of clinical efforts in prostate cancer (PCa) to suppress androgen receptor (AR) signaling by reducing AR ligands (androgen deprivation therapy, ADT), it was recognized that the administration of testosterone (T) to men who have relapsed after ADT (castration-resistant prostate cancer, CRPC) could result in substantial clinical responses. However, these reports were largely anecdotal and remissions were highly variable. In contrast, abundant data from preclinical models have reproducibly shown biphasic responses of hormone-sensitive cancers, whereby at physiological T concentrations proliferation is induced, but at higher, supraphysiological androgen (SPA) concentrations, proliferation is suppressed and in some instances apoptotic programs are engaged. Though often considered to be an in vitro phenomenon of little clinical importance, recent rigorously controlled clinical trials of SPA produced substantial clinical responses in subsets of men with CRPC. Collectively, these findings support studies designed to determine the molecular mechanism(s) driving these responses. Based on these preclinical and clinical findings to date, we hypothesize that the genomic and epigenomic adaptive processes that contribute to CRPC progression also sensitize tumor cells to the differentiation, quiescence and apoptotic programs regulated by the AR under conditions of SPA. We will test this hypothesis through three linked aims: AIM 1. Determine the primary mechanism(s) by which SPA represses CRPC. AIM 2. Define the AR cistrome in prostate cancers reprogrammed by SPA and identify cooperating genes and pathways that are essential or suppressive of SPA effects. AIM 3. Identify drug combinations that synergize with SPA to repress tumor growth and optimize the effects of AR agonism based on a mechanistic understanding of SPA-mediated growth arrest.